Universität zu Köln

Hsin, Chih-hsuan, Stoffel, Marc S., Gazzaz, Malaz, Schaeffeler, Elke, Schwab, Matthias, Fuhr, Uwe and Taubert, Max ORCID: 0000-0001-8925-7782 (2020). Combinations of common SNPs of the transporter gene ABCB1 influence apparent bioavailability, but not renal elimination of oral digoxin. Sci Rep, 10 (1). LONDON: NATURE PUBLISHING GROUP. ISSN 2045-2322

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Abstract

Effects of different genotypes on the pharmacokinetics of probe substrates may support their use as phenotyping agents for the activity of the respective enzyme or transporter. Digoxin is recommended as a probe substrate to assess the activity of the transporter P-glycoprotein (P-gp) in humans. Current studies on the individual effects of three commonly investigated single nucleotide polymorphisms (SNPs) of the ABCB1 gene encoding P-gp (C1236T, G2677T/A, and C3435T) on digoxin pharmacokinetics are inconclusive. Since SNPs are in incomplete linkage disequilibrium, considering combinations of these SNPs might be necessary to assess the role of polymorphisms in digoxin pharmacokinetics accurately. In this study, the relationship between SNP combinations and digoxin pharmacokinetics was explored via a population pharmacokinetic approach in 40 volunteers who received oral doses of 0.5 mg digoxin. Concerning the SNPs 1236/2677/3435, the following combinations were evaluated: CGC, CGT, and TTT. Carriers of CGC/CGT and TTT/TTT had 35% higher apparent bioavailability compared to the reference group CGC/CGC, while no difference was seen in CGC/TTT carriers. No significant effect on renal clearance was observed. The population pharmacokinetic model supports the use of oral digoxin as a phenotyping substrate of intestinal P-gp, but not to assess renal P-gp activity.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hsin, Chih-hsuan UNSPECIFIED UNSPECIFIED UNSPECIFIED Stoffel, Marc S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gazzaz, Malaz UNSPECIFIED UNSPECIFIED UNSPECIFIED Schaeffeler, Elke UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwab, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Fuhr, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED Taubert, Max UNSPECIFIED orcid.org/0000-0001-8925-7782 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-325648
DOI:	10.1038/s41598-020-69326-y
Journal or Publication Title:	Sci Rep
Volume:	10
Number:	1
Date:	2020
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2045-2322
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INTESTINAL P-GLYCOPROTEIN; MDR1 HAPLOTYPES; DRUG INTERACTIONS; POLYMORPHISMS; PHARMACOKINETICS; CYCLOSPORINE; GENOTYPE; IMPACT; DISPOSITION; ABSORPTION Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/32564